Atherosclerosis and associated cardiovascular disease (CVD) are the leading cause of morbidity and mortality in the US. Atherosclerosis is characterized by the accumulation of lipids in the artery wall, and is an inflammatory disease in which several immune effectors including macrophages play a central role. Obesity, insulin resistance, diabetes, and dyslipidemia are all major risk factors for CVD, but the mechanisms that link disordered metabolism to inflammation and the development of atherosclerosis remain to be elucidated. Our published work and preliminary data demonstrate that the double stranded RNA activated protein kinase, PKR, is activated in the context of obesity, where it plays a critica role in driving inflammation and the deterioration of glucose homeostasis. In macrophages, exposure to lipotoxic signals and lipoproteins activate PKR. In addition, PKR is a critical component for the activation of the NLRP3 inflammasome, and stress signaling pathways such as JNK, which are implicated in the pathogenesis of both diabetes and atherosclerosis. In addition, in supporting data presented in this proposal we demonstrate a significant protection against atherosclerotic plaque development in PKR-deficient mice. Based on these findings our overarching hypothesis is that by modulating inflammatory activity, insulin action, and protein synthesis, PKR links cellular stress and metabolic signals to chronic inflammation and atherosclerosis. The experiments described in this proposal will test that hypothesis by determining the role of PKR in the activation and function of macrophages, and by assessing the whole body and macrophage-specific requirement for PKR in the development of atherosclerosis in vivo. This contribution will expand our understanding of the link between nutrient stress and the development of cardiometabolic disease. The innovation of this work lies in investigating a novel approach to atherosclerosis therapy by identifying the mechanistic link between dyslipidemia and inflammatory activation of immune cells.